Authors: María Jimena Salcedo-Arellano, MD, Jun Yi Wang, PhD, Yingratana A. McLennan, BS, Mai Doan, BS, Ana Maria Cabal-Herrera, MD, Sara Jimenez, BS, Marisol W. Wolf-Ochoa, BS, Desiree Sanchez, BS, Pablo Juarez, BS, Flora Tassone, PhD, Blythe Durbin-Johnson, PhD, Randi J. Hagerman, MD, and Verónica Martínez-Cerdeño, PhD (Journal Name, Volume, page#)
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Abstract: Fragile X–associated tremor/ ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological fea- tures of neurodegeneration in fragile X–associated tremor/ ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter dis- ease, iron accumulation, and a proinflammatory state. Objective: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X–associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X–associated tremor/ataxia syndrome.
Methods: We collected cerebral and cerebellar tissue from 15 fragile X–associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral
microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis.
Results: We found intranuclear inclusions in the endo- thelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X–associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capil- laries that contain amyloid β in the cerebral cortex and the rate of disease progression.
Conclusion: We propose microangiopathy as a patho- logic feature of fragile X–associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society
Authors: Sarwat Amina, Carmen Falcone , Tiffany Hong, Marisol Wendy Wolf-Ochoa, Gelareh Vakilzadeh, Erik Allen, Rosalia Perez-Castro, Maryam Kargar, Stephen Noctor and Verónica Martínez-Cerdeño
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Abstract: An alteration in the balance of excitation-inhibition has been proposed as a common characteristic of the cerebral cortex in autism, which may be due to an alteration in the number and/or function of the excitatory and/or inhibitory cells that form the cortical circuitry. We previously found a decreased number of the parvalbumin (PV)+ interneuron known as Chandelier (Ch) cell in the prefrontal cortex in autism. This decrease could result from a decreased number of Ch cells, but also from decreased PV protein expression by Ch cells. To further determine if Ch cell number is altered in autism, we quantified the number of Ch cells following a different approach and different patient cohort than in our previous studies. We quantified the number of Ch cell cartridges—rather than Ch cell somata—that expressed GAT1—rather than PV. Specifically, we quantified GAT1+ cartridges in prefrontal areas BA9, BA46, and BA47 of 11 cases with autism and 11 control cases. We found that the density of GAT1+ cartridges was decreased in autism in all areas and layers. Whether this alteration is cause or effect remains unclear but could result from alterations that take place during cortical prenatal and/or postnatal development.
Authors: Tiffany Hong, Carmen Falcone, Brett Dufour, Sarwat Amina, Rosalia Perez Castro, Jade Regalado, Weston Pearson, Stephen C. Noctor and Verónica Martínez-Cerdeño
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Abstract: Some forms of Autism Spectrum Disorder, a neurodevelopmental syndrome characterized by impaired communication and social skills as well as repetitive behaviors, are purportedly associated with dysregulation of the excitation/inhibition balance in the cerebral cortex. Through human postmortem tissue analysis, we previously found a significant decrease in the number of a gamma-aminobutyric acid (GABA)ergic interneuron sub- type, the chandelier (Ch) cell, in the prefrontal cortex of subjects with autism. Ch cells exclusively target the axon initial segment (AIS) of excitatory pyramidal (Pyr) neurons, and a single Ch cell forms synapses on hundreds of Pyr cells, indicating a possible role in maintaining electrical balance. Thus, we herein investigated this crucial link between Ch and Pyr cells in the anatomy of autism neuropathology by examining GABA receptor protein expression in the Pyr cell AIS in subjects with autism. We collected tissue from the prefrontal cortex (Brodmann Areas (BA) 9, 46, and 47) of 20 subjects with autism and 20 age- and sex-matched control subjects. Immunohis- tochemical staining with antibodies against the GABAA receptor subunit a2 (GABAARa2) – the subunit most prevalent in the Pyr cell AIS – revealed a significantly decreased GABAARa2 protein in the Pyr cell AIS in supra- granular layers of prefrontal cortical areas BA9 and BA47 in autism. Downregulated GABAARa2 protein in the Pyr cell AIS may result from decreased GABA synthesis in the prefrontal cortex of subjects with autism, and thereby contribute to an excitation/inhibition imbalance. Our findings support the potential for GABA receptor agonists as a therapeutic tool for autism! 2020 Published by Elsevier Ltd on behalf of IBRO.
Authors: María Jimena Salcedo-Arellano, MD, Marisol Wendy Wolf-Ochoa, BS, Tiffany Hong, MS, Sarwat Amina, PhD, Flora Tassone, PhD, Mirna Lechpammer, MD, Randi Hagerman, MD, and Verónica Martínez-Cerdeño, PhD
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Abstract: Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is characterized by the presence of ubiquitin-positive inclusions in neurons and astrocytes and by cerebellar tremor and ataxia. Parkinsonism has been reported in FXTAS, but most patients lack the characteristic rest tremor and severe rigidity seen in idiopathic Parkinson’s disease (PD). Objective: To describe the frequency of concomitant PD in FXTAS. Methods: We reviewed the medical record of 40 deceased patients diagnosed with FXTAS and performed a pathology analysis to confirm both FXTAS and PD. Results: Clinical histories indicated that 5 FXTAS patients were diagnosed with idiopathic PD and 2 with atypical parkinsonian syndrome. After pathological examination, we found that 7 patients in the PD clinical diagnosis group had dopaminergic neuronal loss; however, only 2 of 7 presented Lewy bodies (LBs) in the substantia nigra. Therefore, a total of 5% of the 40 cohort patients met the pathologic criteria for the concomitant diagnosis of FXTAS and PD. In addition, 2 patients not clinically diagnosed with PD also had nigral neuronal loss with LBs in substantia nigra. In total 10% of these 40 patients had LBs. Conclusion: This report expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS and the concept that the parkinsonism found in FXTAS is sometimes indistinguishable from PD. We propose that FMR1 should be recognized as one of the exceptional genetic causes of parkinsonism with presynaptic dopaminergic loss and LBs.
Authors: Ma. Jimena Salcedo-Arellano, Randi J. Hagerman and Verónica Martínez-Cerdeño
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Abstract: Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or pre-mutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.
Authors: Verónica Martínez-Cerdeño, Jun Yi Wang, Jim Grigsby, Deborah Hall, and Randi J Hagerman
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Abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is one of the four disorders associated with the fragile X mental retardation 1 (FMR1) gene, that also include fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency and fragile X-associated neuropsychiatric disorders (FXAND). FXTAS, first reported in 2001 (Hagerman et al. 2001), is a neurodegenerative disorder of premutation alleles with between 55 and 200 CGG repeats, while FXS present with expansions larger than 200 CGG repeats. Carriers of premutation alleles are as high as 1 in 130 females and 1 in 250 males. However, only around 40% of male carriers and 14% of female carriers will develop FXTAS (Jacquemont et al. 2004; Rodriguez-Revenga et al. 2009). FXTAS is generally less severe in females because they have a second normal X chromosome that is active in about 50% of neurons and it is therefore protective to the brain. The repeat expansion can increase from one generation to the next, being common to find FXTAS in one generation and FXS in following generations within the same family. Nevertheless, less than half of all premutation carriers develop FXTAS and the reason is not known. As in FXS, the FMR1 premutation is inherited in an X-linked fashion and when the premutation is inherited paternally, it does not expand further outside of the premutation range (Reyniers et al. 1993).
Authors: María Jimena Salcedo-Arellano, Randi J. Hagerman, Verónica Martínez-Cerdeño
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Abstract: El síndrome de temblor y ataxia asociado al X frágil (FXTAS) es una enfermedad neurodegenerativa relaciona- da con la premutación del gen FMR1. Los alelos con premutación (55-200 repeticiones de CGG), al contrario de los alelos con mutación completa (más de 200 repeticiones CGG), tienen una producción excesiva de ARN mensajero y unos niveles normales o reducidos de proteína. El FXTAS afecta al 40% de los hombres y al 16% de las mujeres portadores de la premu- tación de FMR1. Se presenta con una amplia variedad de signos neurológicos, como temblor de intención, ataxia cerebe- losa, parkinsonismo, déficit en la función ejecutiva, neuropatía periférica y deterioro cognitivo que conduce a la demen- cia, entre otros. En esta revisión se presenta lo que hasta ahora se conoce del mecanismo molecular, los hallazgos radiológicos y la patología, así como también la complejidad del diagnóstico y el tratamiento del FXTAS.
Authors: Verónica Martínez Cerdeño, PhD, Tiffany Hong, BS, Sarwat Amina, PhD, Mirna Lechpammer, MD, PhD, Jeanelle Ariza, BS, Flora Tassone, PhD, Stephen C. Noctor, PhD, Paul Hagerman, MD, PhD and Randi Hagerman, MD
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Abstract: Background: Fragile X-associated tremor/ ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress– mediated damage and iron deposition.
Objective: Determine whether the pathology of fragile X- associated tremor/ataxia syndrome involves microglial activation and an inflammatory state.
Methods: Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of micro- glial cells in the putamen of 13 fragile X-associated tremor/ ataxia syndrome and 9 control postmortem cases.
Results: Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X- associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls.
Conclusions: The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syn- drome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration.
Authors: Fang Liu, Kayla Horton-Sparks, Vanessa Hull, Robert W. Li and Verónica Martínez-Cerdeño
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Abstract: Background: Gut microbiota has the capacity to impact the regular function of the brain, which can in turn affect the composition of microbiota. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in gut microbiota; however, it is not yet clear whether the change in the microbiota associated with ASD is a cause or a consequence of the disease.
Methods: We have investigated the species richness and microbial composition in a valproic acid (VPA)-induced rat model autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA genes sequenced using Illumina, and the global microbial co-occurrence network was constructed using a random matrix theory-based pipeline. Collected rat microbiome data were compared to available data derived from cases of autism.
Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community in a pattern similar to that seen in patients with ASD. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA.
Conclusions: Our data on the microbiota of the VPA rat model of autism indicate that this model, in addition to behaviorally and anatomically mimicking the autistic brain as previously shown, also mimics the microbiome features of autism, making it one of the best-suited rodent models for the study of autism and ASD.
Authors: Jeanelle Ariza, BS, Hailee Rogers, BS, Anna Hartvigsen, BS, Melissa Snell, BS, Michael Dill, BS, Derek Judd, BS, Paul Hagerman, MD, PhD and Verónica Martínez-Cerdeño, PhD
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Abstract: Background: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the develop- ment of neurodegenerative diseases. We investigated a potential iron modification in the putamen – a structure that participates in motor learning and performance – in fragile X-associated tremor/ataxia syndrome.
Methods: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl’s method, and iron-binding proteins using immunostaining.
Results: We found increased iron deposition in neuro- nal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron.
Conclusions: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. VC 2017 International Parkinson and Movement Disorder Society
Authors: Verónica Martínez-Cerdeño, PhD, Mirna Lechpammer, MD, PhD, Paul J Hagerman, MD and Randi Hagerman, MD
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Abstract: Letters: New Observations
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